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To be published as:
Maverinck –
At the crossroads:
MR contrast agents.
June 2017.
Aunt Minnie Europe


Rinckside
ISSN 2364-3889

Rinck PA.
At the crossroads:
MR contrast agents.
Rinckside 2019; 30,4: 9-11.



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At the crossroads: MR contrast agents

or thirty years scientific leaders and young researchers in the development of mag­ne­tic re­so­nan­ce con­trast agents have met at biennial conferences arranged by the European Magnetic Resonance Forum (EMRF) and The Round Table Foundation (TRTF).

From the beginning, the attendees comprised both university scientists and representatives from industry. Earlier, these meetings were very attractive for researchers working for the contrast agent manufacturers to present their basic research in a setting that fosters discussion, collaboration, and advancement in the field without being pressured by their sales and marketing departments. However, in the meantime commercial basic and applied research has been drastically cut back, some of the major companies have changed hands, and most companies focus mainly on marketing of generic compounds, some selling products developed by their competitors after the original agent’s patent expiration.

spaceholder red600   The leitmotif of this year's two-day meeting in Mons, Belgium, was "Standing at the Crossroads: 40 Years of MR Contrast Agents" – what has happened in the field during the last 40 years after the first description of MR contrast agents by Paul C. Lauterbur in 1978 [1], what have we learned, what is the state-of-the-art, where will we go to? The conference was organized alternating review lectures of the developments, improvements, challenges, and failures of the last thirty years given by leading experts in the field and presentations of novel theoretical tools, new ideas, and new compounds by young scientists.

The opening lecture was entitled "MR imaging – Quo vadis?" It gave an account of the factors influencing the development of the tech­nique, scientifically, commercially and socially. The talk was not about the development of techniques and great leaps forward in MR imaging coming up soon, but rather it described repercussions and forces from the out­side – realities which during the last 40 years formed MR imaging – and will influence and guide the development in the future. This included its instrumentation and accessories, academic and industrial research, fashions and hypes, global cultural differences, changes within societies and human factors, disruptive technologies, the worldwide market for MR instrumentation and contrast agents, and new paradigms. Excerpts have been published earlier in Rinckside [2].

Among the experts, there was agreement that the domain of medical imaging will be mostly at 1.5 Tesla in Europe, North America, and Japan, and 0.3 to 1.5 Tesla for instance in Russia and China; even in the future, clinical use of ultra-high field equipment at 3 Tesla will be limited and higher fields will be a domain for dedicated scientific research.

An interesting contribution in one of the discussions was the opinion of researchers in the exact sciences that radiologists will only be involved in patient studies with common contrast agents, but not in dedicated MR studies with techniques using novel diagnostic, therapeutic and theragnostic compounds. The reason given is the radiologists’ lack of background in dedicated MR techniques and biochemical interactions of targeted compounds and tracers. Such examinations or interventions would become the domain of other disciplines, e.g., oncologists and neuroscientists, perhaps also specialists in nuclear medicine.

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It is interesting how radiologists are seen by some of the scientists developing the tools for radiology.

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Some remarks went even further – radiologists would concentrate on x-ray CT because it is not as complicated as is MR. More so, artificial intelligence will shift routine image assessment away from radiologists. It is interesting how radiology is seen by some of the scientists developing the tools for radiology. This opinion will not find many friends in the radiological community, but the involvement of non-radiologists is already noticeable for some time.

On the other hand, university researchers should not sit in their ivory towers and develop techniques and compounds that don’t have any relevance for or chance to be used in a routine or even basic research medical environment as Robert N. Muller, one of the European leading scientists in the field, stressed in the closing remarks of the conference. From the onset of a research project, feedback with physicians should be sought so as not to end in blind alleyways.


Gadolinium uptake in the brain

The likely lack of stability of linear Gd-compounds was already heatedly debated at the first conference of this series in 1988 [3, 4], long before the first occurrence of nephrogenic systemic fibrosis (NSF).

Increased signal intensity in plain T1-weighted MR images is observed in a number of brain structures of patients who had undergone several contrast-enhanced studies. These hyperintensities are believed to be induced by tiny amounts of gadolinium held back in the brain. At present, investigations are under way to try to understand how and why Gd is retained in brain and other tissues in the body. Studies focus on the contrast agents’ in vivo stability (combination of equilibrium, kinetic and pharmacokinetic properties), the way how Gd-containing compounds cross biological barriers, the chemical form of the retained compounds (intact contrast agents, or soluble and insoluble Gd-containing compounds), and the relationship between Gd-compounds and local image hyperintensities.

These studies open new avenues beyond the potential toxicity of the used Gd-complexes since they allow to get advanced insights into thermodynamics and kinetics of metal containing preparations in living systems [5].

Possibly still unknown physiological-biochemical pathways allowing gadolinium to pass the blood-brain-barrier are discussed by some researchers, but nobody at this conference presented any supporting evidence of such ideas.

My personal explanation of the uptake of gadolinium dates back to research done by our group in the 1980s, even before gadolinium agents entered the market. In a patient population of some 450 with definite, probable, and possible multiple sclerosis (MS) referred to us for MRI, some 40 suffering from definite MS were chosen randomly for relaxation time measurements of plaque-free grey and white matter. Overall white matter T2 was slightly higher in MS patients than in a non-MS population. These changes do not influence image contrast and are not visible in MR images [6].

However, it is known that in many different brain diseases localized or general breakdown of the blood-brain-barrier (BBB) can be observed – among them MS, Alzheimer's disease, epilepsy, amyotrophic lateral sclerosis (ALS), edema but also stroke and brain injuries as well as systemic diseases, such as liver failure. Work with animal models of disease and with cell culture BBB models has enabled the identification of some of the molecular mechanisms that cause changes to the BBB [7].

Thus, diminutive amounts of gadolinium may enter the brain in such patients and, after multiple applications of a Gd-based contrast agent, slowly accumulate and visibly change MR image contrast.

In the discussion of this topic it was also criticized that patents on contrast agents and accessories and the enforcement of poor quality patents by patent trolls, e.g. on contrast-enhanced MR angiography, have had a negative impact on the development of better and safer agents.


Signal and contrast enhancement

Another area of interest was the intrinsic insensitivity of MRI and possibly boosting procedures with unspecific or targeted molecules or techniques.

Overviews and new ideas covered the whole spectrum of prospects, from optimizing the relaxivity of existing or possible compounds, the use of CEST (Chemical Exchange Saturation Transfer) agents or hyperpolarized (HP) molecules providing the possibility of investigating in vivo metabolic processes.

Hyperpolarization requires specific and expensive additional equipment which makes it ill suited for routine clinical tasks. Hyperpolarized gases can be used for lung imaging, but the application of perfluorinated gases might be more practicable. As with CEST, additional hard- and software have to be installed.

New classes of contrast agents with relaxivities several hundred percent higher than today’s agents in clinical use below 2 Tesla have been proposed; however, safety and stability of these complexes has not yet been examined in animals and humans. They might be necessary for ultra-high field research applications, mostly for animal experiments, where bigger contrast agent molecules will provide better relaxivity.


Targeting

Targeted theragnostic compounds were proposed in an unpublished description by Paul C. Lauterbur already in 1977.

However, few have reached the clinical level, among them one novel project in France involving nanoparticles made of polysiloxane and gadolinium chelates. In a clinical phase Ib trial it has been shown that after intravenous administration they accumulate in tumors and act as a radiosensitizer to increase locally the effect of radiotherapy, for instance for the treatment of multiple brain metastases by whole brain irradiation. Their biodistribution and the accumulation in the tumor can be followed by MRI due to the presence of gadolinium.

It remains to be seen which of the hundreds of different projects will leave the labs of the research institutes and will be turned into routine patient applications. At present, we are using MR contrast agents introduced 25-30 years ago.

spaceholder red600   The respective abstracts of the talks mentioned can be found in the Book of Abstracts. It is available free of charge at the TRTF website.

spaceholder red600   Last, but not least: The participants of the conference received an offprint from EMRF’s MR textbook: "An Excursion into the History of Magnetic Resonance Imaging." It can be downloaded free of charge from here.


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References

1. Lauterbur PC, Mendonça-Dias MH, Rudin AM. Augmentation of tissue water proton spin-lattice relaxation rates by in vivo addition of paramagnetic ions. Frontiers of Biological Energetics 1978; 1: 752-759.
2. Rinck PA. MR imaging: Quo vadis? Rinckside 2019; 30,3: 5-8.
3. Meyer D, Schaefer M, Doucet D. Physico-chemical properties of the macrocyclic chelate Gadolinium-DOTA. in: Rinck PA (ed). Contrast and contrast agents in magnetic resonance imaging. Proceedings of Contrast and Contrast Agents in Magnetic Resonance Imaging – A Special Topic Seminar; Trondheim, Norway; 12-13 September 1988. Trondheim and Mons: The European Workshop on Magnetic Resonance in Medicine (EMRF). 1989. 33-43.
4. Tweedle MF. Work in progress toward nonionic macrocyclic gadolinium (III) complexes. in: Rinck PA (ed). Contrast and contrast agents in magnetic resonance imaging. Proceedings of Contrast and Contrast Agents in Magnetic Resonance Imaging – A Special Topic Seminar; Trondheim, Norway; 12-13 September 1988. Trondheim and Mons: The European Workshop on Magnetic Resonance in Medicine (EMRF). 1989. 65-73.
5. Gianolio E, Di Gregorio E, Aime S. Chemical insights into the issues of Gd retention in the brain and other tissues upon the administration of Gd‐containing MRI contrast agents. European Journal of Inorganic Chemistry 2019; 2: 137-151.
6. Rinck PA, Appel B, Moens E. Relaxation-time measurements of the white and gray substances in multiple sclerosis patients [Article in German]. Fortschr Röntgenstr 1987; 147: 661-663.
7. Daneman R. The blood-brain barrier in health and disease. Ann Neurol 2012; 72: 648-672.

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